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First, cause-specific death was not available in this study. Second, RKF measurement is not accurate given the use of CL_urea and not the average of renal urea and creatinine clearances and the difficulties in complete collection of urine samples and its punctuality in patient daily life. The use of factor 0.9 for predialysis serum urea nitrogen for renal CL_urea calculation might have also induced errors to some extent. Nevertheless, the population-level associations with clinical outcomes can be estimated from an adequate number of subjects if such errors are not associated with the outcome. Third, available RKF measures may not be representative of those in the entire hemodialysis population, because patients on dialysis with limited or no RKF are less likely to have undergone urine collections, especially at 1 year after hemodialysis initiation. This potential selection bias might have resulted in missing patients who lost RKF during the first 1 year of dialysis, and thus, the mortality risk of RKF decline might be underestimated. Additionally, although we adjusted for only baseline patient characteristics and not those at year 1 to avoid overadjustment, RKF decline could also be an intermediary between adverse events (e.g., cardiovascular events and infection) during the first year of dialysis and subsequent mortality. Indeed, the mortality risk of RKF decline was attenuated to some extent after adjusting for body mass index and laboratory variables at both baseline and 1 year, but it still remained significant (data not shown). Although it is hard to estimate the net effect of the former and the latter limitations, our results met seven of nine of the criteria by Hill 38 (i.e., temporal relationship, strength, dose-response relationship, consistency, biologic plausibility, coherence, and reasoning by analogy), suggesting a possible causal relationship between RKF decline and all-cause death in patients on hemodialysis. Continue reading “We acknowledge other constraints in this studies”